Two-compartment model

Typical plasma concentration (Cp) versus time profiles for a

drug that obeys a two-compartment model following
intravenous bolus administration

y axis: normal scale y axis: logarithmic scale

 A schematic representation of
X1 X2 three types of two-compartment
models consisting of a central
and a peripheral compartment.

Please note the difference in

each type is reflected in the
X1 X2 placement of an organ
responsible for the elimination
of the drug from the body. K12,
K21, transfer rate constants;
K10, K20, elimination rate
constants.
X1 X2
 Assumptions of the model
• Upon drug absorption there is instantaneous
distribution of drug throughout the central
compartment (sampling compartment) having a
volume V1 (Vc)
• Transfer of drug from the central compartment to
the peripheral compartment is by a first-order
process
• Transfer of drug from the peripheral
compartment to the central compartment is by a
first-order process
 One Compartment Two Compartments

Distribution equilibrium
Rapid or prompt
is slow (takes finite
equilibrium is attained.
time).

Distribution and post-

There is a single
distribution are two
disposition phase
distinct phases.

Linear: drug elimination Linear: distribution and

follows first order elimination both follow
kinetics first order
 Drug concentrations in the two compartments
following a single i.v. bolus injection

A. We start with virtually

no drug in the second
compartment, but re-
equilibration moves
drug in – levels rise
B. A brief equilibrium - no
net movement – at the
peak of the curve,
levels are neither rising
nor falling
C. Re-equilibration moves
into reverse and drug
leaves the second
compartment – levels
fall
 K12
X1 X2
K21

K10

dX 1
 K 21 X 2  K12 X 1  K10 X 1
dt
dX 2
 K12 X 1  K 21 X 2
dt
Distribution rate from X1 to X2 = K12 X 1
Distribution rate from X2 to X1 = K 21 X 2
Elimination rate =
K10 X 1
 X 0 (  K 21 ) t X 0 ( K 21   )  t Amount in the
X1  e  e central compartment
   
X 0 (  K 21 ) t X 0 ( K 21   )  t Conc in the central
C1  e  e compartment
VC (   ) VC (   )
VC is the volume of the central compartment
t  t
C1  Ae  Be
Xo(  K 21) Xo( K 21   )
A B
Vc(   ) Vc(   )

XoK 12  βt Amount in the

X2  (e  e αt ) peripheral compartment
(α  β)
 Determination of the postdistribution
rate constant (β) and the
coefficient (B)
• Postdistributio
n phase to
determine:
1. Determine β
from the graph
by using the
slope
2. The y-axis
intercept of the
extrapolated line
is B
 Determination of the
distribution rate constant (α) and
the coefficient (A)
• Method of residuals: The
difference between
measured concentrations
and those obtained by
extrapolation of the post-
distribution line is plotted
vs time
1. Determine α from the
graph by using the slope
2. The y-axis intercept of
the extrapolated line is A
 Determination of micro rate constants: the inter-
compartmental rate constants (K21 and K12) and
the pure elimination rate constant (K10)

Aβ  Bα
K 21 
(A  B)
αβ
K10 
K 21

K12  α  β-K 21- K10

Volume of distribution of the central
compartment (VC)
• Volume of distribution of the central
compartment (VC). This is a proportionality
constant that relates the amount of drug
and the plasma concentration immediately
(i.e. at t=0) following the administration of
a drug.
Xo
Vc 
A B
 Volume of distribution during the
terminal phase (Vb or Vβ)
• This is a proportionality constant that
relates the plasma concentration and the
amount of drug remaining in the body at a
time following the attainment of distribution
equilibrium, or at a time on the terminal
linear portion of the plasma concentration
time data
K 10Vc
V 

 Volume of distribution at steady
state (Vss)
• This is a proportionality constant that
relates the plasma concentration and the
amount of drug remaining in the body at a
time, following the attainment of practical
steady state. This volume of distribution is
independent of elimination parameters
such as K10 or drug clearance.
Xss  ( K 21  K 12) 
Vss    Vc
Css  K 21 
 The area under the plasma
concentration time curve (AUC)
• Model independent: Trapezoid method
• Model dependent:
 
 
t  t
AUC  C (t ).dt  Ae  Be .dt
0 0

A B
AUC  
 
Example: The pharmacokinetics of amrinone after a single
IV bolus injection (75 mg) in 14 healthy adult male
volunteers followed a two-compartment open model and fit
the following parameters:
A = 4.62 ± 12.0 µg/mL
B = 0.64 ± 0.17 µg/mL
 = 8.94 ± 13 hr–1
 = 0.19 ± 0.06 hr–1
From these data, calculate:
a. The volume of the central compartment
b. The volume of the tissue compartment
c. The transfer constants k12 and k21
d. The elimination rate constant from the central compartment
e. The elimination half-life of amrinone after the drug has
equilibrated with the tissue compartment
Two Compartment Extravascular

Ka K12
Xa X1 X2
K21

K10

dX 1
 K a X a  K 21 X 2  K12 X 1  K10 X 1
dt
dX 2
 K12 X 1  K 21 X 2
dt
Two Compartment Extravascular

Ka K12
Xa X1 X2
K21

K10

t  t t
C1  Ae  Be  Ce

A B  C